tbuckley/cabot-search huggingface dataset:
Abstract 747: Deciphering tumor ecosystems at super-resolution from spatial transcriptomics
Authors: Jian Hu, Kyle Coleman, Edward B. Lee, Humam Kadara, Linghua Wang, Mingyao Li
Journal: Cancer Research (2022)

Abstract The tumor microenvironment (TME) contains networks of cells and structures that surround tumor cells. Cell populations in the TME, including their abundance, composition, and spatial location are critical determinants of the occurrence, growth, and metastasis of a tumor. A comprehensive analysis of the multiple exchanges between tumor cells and their TME is essential for understanding the underlying mechanisms of tumor growth and response to anti-cancer therapies. Recent advances in spatially resolved transcriptomics (SRT) techniques have enabled gene expression profiling while preserving location information in tissues, which innovates a promising avenue to study the TME in a spatial context. With the power of SRT, we aim to provide a detailed annotation of tumor structure and different lymphocytes by integrating gene expression information and cell morphology features in the complemented high-resolution histology image obtained from the same tissue section. A major challenge that hinders gene expression and histology integration in SRT data is the relatively low resolution of gene expression data compared to pixel-resolution histology images. As gene expression is only measured in discrete spots that are separated by tissue gaps, a large proportion of the tissue area remains unmeasured (e.g., &amp;gt;50% in 10x Visium). The incomplete coverage of gene expression in ST has prevented the deciphering of detailed TME structures such as the tertiary lymphoid structure (TLS).To overcome this challenge, we present TESLA (Tumor Edge Structure and Lymphocyte multi-level Annotation), a machine learning framework that integrates gene expression and histology image in SRT to investigate the detailed strictures in TME. TESLA first fills in the gene expression for unmeasured areas and generates gene expression images in the same resolution as the histology image. Next, TESLA integrates the gene images with the histology image to annotate different tumor/TME cell types at pixel resolution. Some specific tumor-infiltrating lymphocytes structures, such as TLSs, can also be detected by colocalization analysis of different lymphocytes. TESLA is also able to characterize high-resolution cellular and molecular spatial structures of tumor by separating tumor into different subtype regions and elucidating differential transcriptome programs. The detailed multi-level annotations performed by TESLA provide a comprehensive understanding of the spatial context and the nature of cellular heterogeneity of the TME. Citation Format: Jian Hu, Kyle Coleman, Edward B. Lee, Humam Kadara, Linghua Wang, Mingyao Li. Deciphering tumor ecosystems at super-resolution from spatial transcriptomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 747.
Risk scoring system for the preprocedural prediction of the clinical failure of peroral endoscopic myotomy: a multicenter case–control study
Authors: Hirofumi Abe, Shinwa Tanaka, Hiroki Sato, Yuto Shimamura, Hiroki Okada, Junya Shiota, Chiaki Sato, Hiroyuki Sakae, Masaki Ominami, Yoshitaka Hata, Hisashi Fukuda, Ryo Ogawa, Jun Nakamura, Tetsuya Tatsuta, Yuichiro Ikebuchi, Hiroshi Yokomichi, Haruhiro Inoue
Journal: Endoscopy (2022)

Peroral endoscopic myotomy (POEM) is effective for the management of achalasia and its variants; however, it can be ineffective in some patients. We aimed to develop and validate a risk scoring system to predict the clinical failure of POEM preoperatively.Consecutive patients who underwent POEM in 14 high volume centers between 2010 and 2020 were enrolled in this study. Clinical failure was defined as an Eckardt score of ≥ 4 or retreatment. A risk scoring system to predict the short-term clinical failure of POEM was developed using multivariable logistic regression and internally validated using bootstrapping and decision curve analysis.Of the 2740 study patients, 112 (4.1 %) experienced clinical failure 6 months after POEM. Risk scores were assigned for three preoperative factors as follows: preoperative Eckardt score (1 point), manometric diagnosis (-4 points for type II achalasia), and a history of prior treatments (1 point for pneumatic dilation or 12 points for surgical/endoscopic myotomy). The discriminative capacity (concordance statistics 0.68, 95 %CI 0.62-0.72) and calibration (slope 1.15, 95 %CI 0.87-1.40) were shown. Decision curve analysis demonstrated its clinical usefulness. Patients were categorized into low (0-8 points; estimated risk of clinical failure < 5 %) and high risk (9-22 points; ≥ 5 %) groups. The proportions of clinical failure for the categories were stratified according to the mid-term outcomes (log-rank test, P < 0.001).This risk scoring system can predict the clinical failure of POEM preoperatively and provide useful information when making treatment decisions.
Abstract 2381: Interleukin-4 receptor signaling induces glycolysis in triple negative breast cancer
Authors: Demond Williams, Wendy Bindeman, Ebony Hargrove-Wiley, Barbara Fingleton
Journal: Cancer Research (2022)

Abstract In the context of cancer biology Th2 cytokines such as IL4 and IL13 are most studied for their effects on immune cells such as macrophages. IL-4 receptor is established to cause polarization of macrophages to a pro-tumor M2 phenotype. While much is known about the signaling effects of IL-4 in immune cells there is relatively little known about its effects in cancer cells that express the receptor. Our lab has established a role of signaling in IL4 receptor expressing cancer cells for promoting metastasis. Many of the effects of IL-4 signaling in immune cells are accompanied by metabolic changes. Thus, we aimed to study the effects of IL-4 signaling on metabolism in breast cancer to better understand how these metabolic changes might induce metastatic phenotypes associated with IL-4 stimulation. IL-4 increased glucose uptake in multiple human TNBC cell lines assessed via NBDG uptake assay. Production of lactate was also significantly increased as assessed by colorimetric assay. We then became interested in possible alterations in metabolism downstream of increased glucose uptake. By Seahorse assay we found that IL-4 significantly increased glycolysis, as well as mitochondrial metabolism when assessed by ATP Rate assay. By metabolic flux using C13 labeled glucose we found that IL-4 increased incorporation of carbon from glucose into lactate while not having a significant effect on TCA cycle intermediates. This led us to question whether IL-4 may affect other arms of metabolism that feed into TCA cycle and mitochondrial metabolism. We looked at how IL4 impacts glutaminolysis and found that IL-4 stimulation leads to increased expression of glutamine transporter ASCT2, as well as increased glutamine uptake. We have begun to examine whether these metabolic changes affect epigenetic regulation. Initial data indicates that IL4 treatment leads to increased histone acetylation in TNBC cell lines. Citation Format: Demond Williams, Wendy Bindeman, Ebony Hargrove-Wiley, Barbara Fingleton. Interleukin-4 receptor signaling induces glycolysis in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2381.
Abstract 6121: Correlation of tumor immune microenvironment status and driver genes alterations in Chinese non-small-cell lung cancer patients
Authors: Jindong Guo, Liwen Xiong, Haibin Yuan, Mengna Hu, Bei Zhang, Ding Zhang
Journal: Cancer Research (2022)

Abstract Background: Patients with different driver genes show a variety of immunotherapy efficacy for non-small-cell lung cancer (NSCLC). In addition to PD-L1, the evaluation of the immune microenvironment contributes to a deeper understanding of the mechanisms of immunotherapy resistance. Methods: Tumor tissues from 2674 NSCLC patients were collected. Genetic alterations were profiled using targeted next-generation sequencing with 733 cancer-related genes panel. Immunohistochemistry was used to evaluate the PD-L1 tumor proportion score, (TPS) expression on the surface of tumor cells. Tumor-infiltrating immune cells of 120 tumor samples were labeled with multiple immunofluorescence staining. Results: Overall, CD8+ T cell infiltration level was negatively associated with both EGFR copy number gain (CNG, p &amp;lt; 0.001) and ERBB2 CNG (p = 0.021). Also, the presence of EGFR or ERBB2 CNG was related with fewer natural killer cell infiltration (EGFR: p &amp;lt; 0.001; ERBB2: p = 0.036) and a lower M1/M2 tumor-associated macrophages ratio compared to wild-type tumors (EGFR: p = 0.051; ERBB2: p = 0.036), suggesting a relatively weaker anti-tumor ability. In addition, we noted that KRAS CNV was negatively related to M2 macrophages (p = 0.027). Patients carrying ALK translocation (p &amp;lt; 0.001), ROS1 translocation (p = 0.006), KRAS mutations (p &amp;lt; 0.001) and MET (p &amp;lt; 0.001) mutations had the elevated PD-L1 TPS expressions, while those harboring EGFR (p &amp;lt; 0.001) and ERBB2 mutations (p = 0.001) had lower PD-L1 expression. Compared to the other EGFR mutations, PD-L1 expression in EGFR CNG tumors was higher, and no significant differences were found between CNG and other types of mutation in patients harboring ERBB2, KRAS, MET alterations. Conclusion: NSCLC patients with EGFR CNG and ERBB2 CNG had fewer invasion of cytotoxic T cells and NK cells and a lower M1/M2 macrophages ratio. EGFR CNG may intensively modify the tumor immune microenvironment, which is a possible mechanism contributing to EGFR-TKI resistance. Citation Format: Jindong Guo, Liwen Xiong, Haibin Yuan, Mengna Hu, Bei Zhang, Ding Zhang. Correlation of tumor immune microenvironment status and driver genes alterations in Chinese non-small-cell lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6121.
Abstract 6046: Targeting TBL1 inhibits nuclear β-catenin activity and enhances immune checkpoint inhibition efficacy in osteosarcoma
Authors: Kengo Nakahata, Bikesh K. Nirala, Ryan L. Shuck, Lyazat Kurenbekova, Jason T. Yustein
Journal: Cancer Research (2022)

Abstract Background: Osteosarcoma (OS) is the most common bone malignancy in childhood and adolescence. Though the prognosis of OS patients has been improved by multimodal therapies, patients with metastatic disease still have a very poor prognosis. We previously reported a novel TBL1/β-catenin inhibitor, Tegavivint, suppresses OS primary tumor and lung metastasis using patient-derived cell lines. Wnt/β-catenin signaling is reported to influence intratumoral T cell infiltration and using murine syngeneic OS models we investigated the effects of Tegavivint on improving immune checkpoint inhibition and the OS tumor immune microenvironment. Methods: We used murine OS cell lines F331 and F420 for in vitro and in vivo studies. We performed cytotoxicity studies using the CCK-8 assay and western blots to investigate downstream β-catenin signaling perturbations secondary to Tegavivint. Intratibial injections were performed into C57BL/6 mice using both murine cell lines. Tegavivint and anti-PD-1 antibody was administered as monotherapy or in combination. After treatment, we compared the tumor volume in the control, monotherapy (Tegavivint or PD-1 only) and combination therapy groups (Tegavivint and PD-1). We assessed T cell tumor infiltration using immunohistochemistry and flow cytometry. Results: In vitro, Tegavivint suppresses the growth of F331 and F420 cell lines with IC50s of 9.52nM and 49.4nM, respectively after 72hours of treatment. In vivo, anti-PD1 monotherapy did not show any significant anti-tumor activity, but Tegavivint monotherapy significantly suppressed the growth of murine tumors (p&amp;lt;0.05) and the combination therapy further improved overall anti-tumor activity. IHC staining showed an increase in CD8-positive T cells in Tegavivint monotherapy and combination therapy treated tumors compared with the control tumors. Furthermore, flow cytometry validated the increase in CD8-positive T cell infiltration and also showed an increase in intratumoral NK cells in Tegavivint treated tumors. Conclusions: These results indicate that TBL1 inhibition, via Tegavivint, inhibits nuclear β-catenin activity and alters the tumor immune microenvironment and enhances immune checkpoint blockade in OS. Future directions include more comprehensive profiling and molecular analysis of the tumor and immune microenvironment, and evaluation of additional immune modulatory approaches for the treatment of OS. Citation Format: Kengo Nakahata, Bikesh K. Nirala, Ryan L. Shuck, Lyazat Kurenbekova, Jason T. Yustein. Targeting TBL1 inhibits nuclear β-catenin activity and enhances immune checkpoint inhibition efficacy in osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6046.
Abstract 5336: Dissecting the molecular mechanism of trastuzumab resistance in stage IV HER2-positive gastric cancer patients
Authors: Qi Xu, Jingjing Li, Haimeng Tang, Hua Bao, Junrong Yan, Xue Wu, Yang Shao, Jianying Jin, Cong Luo, Haimin Weng, Jieer Ying
Journal: Cancer Research (2022)

Abstract Introduction: The effect of trastuzumab in targeted therapy for HER2-positive gastric cancer (GC) is limited by the eventual development of resistance within patients. Although numerous studies have been published on this topic, both the mechanism of innate and acquired trastuzumab resistance are still not fully understood. In this study, we compare the mutational landscape of paired solid tumor samples before and after treatment in an effort to identify acquired events associated with resistance. Methods: We performed whole-exome sequencing on 46 tumor and 23 whole blood samples from patients with stage IV gastric cancer were obtained from before treatment (n = 23) and at disease progression (PD) (n = 23). HER2 status was checked using immunohistochemistry and validated with florescence in situ hybridization (FISH). Correlation analysis was then conducted between the mutational profile and clinical data of patients. Results: Comparisons between innate resistance samples and acquired resistance samples at baseline revealed three copy number variation events (CDK12 amplification, ERBB2 amplification, MECOM amplification) that occurs in significantly different proportions (p &amp;lt; 0.05). In addition, for baseline samples, MECOM was shown to be associated with poor progression-free survival (PFS) (Hazard Ratio (HR), 12; 95% CI, 1.6 - 85; p = 0.027). Commonly acquired events (i.e., lacking in before treatment samples and present at PD) within patients include TP53 mutation, MYC amplification, MCL1 amplification, CDKN2A/2B deletion, and CCNE1 amplification. Of these, patients with MCL1 gene amplification had worse survival (HR, 4.8; 95% CI, 1.2 - 20; p = 0.050) than patients with wild-type MCL1. In addition, the NOTCH pathway acquired mutations in 4 of 23 patients and was found to be correlated with a worse PFS (HR, 5.1; 95% CI, 1.4 - 19; p = 0.023), indicating that this pathway is possibly involved with trastuzumab resistance to some degree. Conclusion: Overall, our results show that comparisons of samples obtained before treatment and at PD can give insight about innate and acquired resistance mechanisms to trastuzumab in stage IV, HER2-positive GC patients. Citation Format: Qi Xu, Jingjing Li, Haimeng Tang, Hua Bao, Junrong Yan, Xue Wu, Yang Shao, Jianying Jin, Cong Luo, Haimin Weng, Jieer Ying. Dissecting the molecular mechanism of trastuzumab resistance in stage IV HER2-positive gastric cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5336.
Abstract 590: Humanized PD-1/LAG-3 mice for preclinical evaluation of combination therapy
Authors: Feifei Duan, Xiaoliu Yang, Cunxiang Ju, Jing Zhao, Xiang Gao, Santi Suryani Chen
Journal: Cancer Research (2022)

Abstract Lymphocyte activation gene 3 (LAG-3) is a member of the immunoglobulin superfamily which shares homolog with CD4 and binds to MHC II with higher affinity. It is expressed on activated T cells, regulatory T cells (Tregs), natural killer cells and plasmacytoid dendritic cells, and inhibits their activation. Blocking LAG-3 activity is expected to provide therapeutic benefits in the treatment of cancer, especially when combined with PD-1 blockade. Due to the low homology between human and mouse LAG-3 and PD-1 and in order to enable increased translatability of preclinical in-vivo efficacy evaluation of immune checkpoint antibodies, we generated double humanized mice by replacing the extracellular domain of mouse LAG-3 and PD-1 with the corresponding human sequences. Homozygous double humanized mice express chimeric LAG-3 and PD-1 at comparable levels to mouse LAG-3 and PD-1 respectively in wildtype mice. When treated with human LAG-3 antibody (anti-LAG-3) or human PD-1 antibody (anti-PD-1), CT26 tumor growth was inhibited in a dose-dependent manner, proving that both humanized proteins are functional. However, not all tumor types respond to anti-LAG-3 or anti-PD-1 the same. To identify the suitable tumor models for preclinical efficacy evaluation of anti-LAG-3 and anti-PD-1 combo therapy, we engrafted several syngeneic tumor models onto our mice. The growth of subcutaneously engrafted MC38 colon tumor was mildly inhibited by anti-PD-1, but strongly inhibited in the presence of anti-LAG-3. Similarly, B16F10 melanoma tumor showed modest growth inhibition when treated with anti-PD-1 or anti-LAG-3 separately, while combination therapy significantly repressed tumor growth. However, neither monotherapies of anti-LAG-3 and anti-PD-1 nor combination treatment effectively inhibited tumorigenesis of LLC1 derived lung cancer, indicating that this tumor is likely insensitive to PD-1 and LAG-3 blockade. Collectively, these data indicate that double humanized PD-1 and LAG-3 mice are a powerful tool to evaluate the therapeutic efficacies of anti-hPD-1 and anti-hLAG-3 treatment in different types of tumor in vivo. Citation Format: Feifei Duan, Xiaoliu Yang, Cunxiang Ju, Jing Zhao, Xiang Gao, Santi Suryani Chen. Humanized PD-1/LAG-3 mice for preclinical evaluation of combination therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 590.
Kinetics of basophil hyporesponsiveness during short-course peanut oral immunotherapy
Authors: Michael D. Kulis, Johanna M. Smeekens, Caitlin Burk, Xiaohong Yue, Rishu Guo, Kelly A. Orgel, Ping Ye, Lauren Herlihy, Deanna Hamilton, Quefeng Li, Corinne Keet, Wayne Shreffler, Brian P. Vickery, A. Wesley Burks, Edwin H. Kim
Journal: Journal of Allergy and Clinical Immunology (2022)
Analysis of mortality metrics associated with a comprehensive range of disorders in Denmark, 2000 to 2018: A population-based cohort study
Authors: Oleguer Plana-Ripoll, Julie W. Dreier, Natalie C. Momen, Anders Prior, Nanna Weye, Preben Bo Mortensen, Carsten B. Pedersen, Kim Moesgaard Iburg, Maria Klitgaard Christensen, Thomas Munk Laursen, Esben Agerbo, Marianne G. Pedersen, Jørgen Brandt, Lise Marie Frohn, Camilla Geels, Jesper H. Christensen, John J. McGrath
Journal: PLoS Medicine (2022)

The provision of different types of mortality metrics (e.g., mortality rate ratios [MRRs] and life expectancy) allows the research community to access a more informative set of health metrics. The aim of this study was to provide a panel of mortality metrics associated with a comprehensive range of disorders and to design a web page to visualize all results.In a population-based cohort of all 7,378,598 persons living in Denmark at some point between 2000 and 2018, we identified individuals diagnosed at hospitals with 1,803 specific categories of disorders through the International Classification of Diseases-10th Revision (ICD-10) in the National Patient Register. Information on date and cause of death was obtained from the Registry of Causes of Death. For each of the disorders, a panel of epidemiological and mortality metrics was estimated, including incidence rates, age-of-onset distributions, MRRs, and differences in life expectancy (estimated as life years lost [LYLs]). Additionally, we examined models that adjusted for measures of air pollution to explore potential associations with MRRs. We focus on 39 general medical conditions to simplify the presentation of results, which cover 10 broad categories: circulatory, endocrine, pulmonary, gastrointestinal, urogenital, musculoskeletal, hematologic, mental, and neurologic conditions and cancer. A total of 3,676,694 males and 3,701,904 females were followed up for 101.7 million person-years. During the 19-year follow-up period, 1,034,273 persons (14.0%) died. For 37 of the 39 selected medical conditions, mortality rates were larger and life expectancy shorter compared to the Danish general population. For these 37 disorders, MRRs ranged from 1.09 (95% confidence interval [CI]: 1.09 to 1.10) for vision problems to 7.85 (7.77 to 7.93) for chronic liver disease, while LYLs ranged from 0.31 (0.14 to 0.47) years (approximately 16 weeks) for allergy to 17.05 (16.95 to 17.15) years for chronic liver disease. Adjustment for air pollution had very little impact on the estimates; however, a limitation of the study is the possibility that the association between the different disorders and mortality could be explained by other underlying factors associated with both the disorder and mortality.In this study, we show estimates of incidence, age of onset, age of death, and mortality metrics (both MRRs and LYLs) for a comprehensive range of disorders. The interactive data visualization site (https://nbepi.com/atlas) allows more fine-grained analysis of the link between a range of disorders and key mortality estimates.